SOMATIC MUTATIONS AT FRAGILE ENHANCERS OF LINEAGE- IDENTITY EPITHELIAL GENES IN BREAST CANCER.

Prior research established that double-strand breaks (DSBs) in normal mammary cells are not randomly distributed, but cluster at specific sites including gene promoters. Our lab identified paused RNA polymerase II and topoisomerase2B as key contributors to DSB formation at specific promoters, and further demonstrated that errors in end-joining during DSB repair lead to chromosome translocations observed in breast cancer patients. We hypothesized that specific functions at given genomic regions and local generation and repair of DNA damage are mechanistically linked, leading to the co-evolution of specific gene-regulatory networks and DNA-repair pathways. We focused on regions putatively repaired by the most accurate DNA damage repair pathway (homologous recombination, HR), hypothesizing that it would safeguard functionally relevant regions of the genome. With this approach we identified a unique class of CtIP-bound active enhancers, which share the consensus motif of the GRHL1/2 transcription factors and are involved in the establishment and maintenance of the epithelial phenotype. We found that GRHL1/2 bind to these enhancers and recruit CtIP, linking recruitment of pioneering epithelial transcription factors to HR repair pathway. Indeed, HR-deficient patients showed increased frequency of APOBEC-mediated mutations at CtIP-bound enhancers, possibly leading to altered expression of their target genes and epithelial-to-mesenchymal transition (EMT).

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2025

Author dc:creator

• CIACCI, LORENZO

Contributors dc:contributor

• tutor: P.G. Pelicci; added supervisor: G.I. Dellino; internal advisor: G. Natoli phd coordinator: D. Pasini
• L. Ciacci
• PELICCI, PIER GIUSEPPE
• PASINI, DIEGO

• DNA damage
• chromatin
• enhancer
• topology
• ChIP
• HiChIP
• BLISS
• Settore MED/04 - Patologia Generale

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/ciacci-lorenzo_phd2025-01-21
10.13130/ciacci-lorenzo_phd2025-01-21

OAI identifier oai:identifier

oai:air.unimi.it:2434/1127823